Medicine and Health Sciences Commons^™

Genome-Wide Association Identifies A Common Variant In The Reelin Gene That Increases The Risk Of Schizophrenia Only In Women, Sagiv Shifman, Martina Johannesson, Michal Bronstein, Sam X. Chen, David A. Collier, Nicholas J. Craddock, Kenneth S. Kendler, Tao Li, Michael C. O'Donovan, F. Anthony O'Neill, Michael J. Owen, Dermot Walsh, Daniel R. Weinberger, Cuie Sun, Jonathan Flint, Ariel Darvasi

Psychiatry Publications

Sex differences in schizophrenia are well known, but their genetic basis has not been identified. We performed a genome-wide association scan for schizophrenia in an Ashkenazi Jewish population using DNA pooling. We found a female-specific association with rs7341475, a SNP in the fourth intron of the reelin (RELN) gene (p = 2.9 × 10−5 in women), with a significant gene-sex effect (p = 1.8 × 10−4). We studied rs7341475 in four additional populations, totaling 2,274 cases and 4,401 controls. A significant effect was observed only in women, replicating the initial result (p = 2.1 × 10−3 in …

Morphine Exacerbates Hiv-1 Tat-Induced Cytokine Production In Astrocytes Through Convergent Effects On [Ca2+]I, Nf-Κb Trafficking And Transcription, Nazira El-Hage, Annadora J. Bruce-Keller, Tatiana Yakovleva, Igor Bazov, Georgy Bakalkin, Pamela E. Knapp, Kurt F. Hauser

Pharmacology and Toxicology Publications

Astroglia are key cellular sites where opiate drug signals converge with the proinflammatory effects of HIV-1 Tat signals to exacerbate HIV encephalitis. Despite this understanding, the molecular sites of convergence driving opiate-accelerated neuropathogenesis have not been deciphered. We therefore explored potential points of interaction between the signaling pathways initiated by HIV-1 Tat and opioids in striatal astrocytes. Profiling studies screening 152 transcription factors indicated that the nuclear factor-kappa B (NF-κB) subunit, c-Rel, was a likely candidate for Tat or Tat plus opiate-induced increases in cytokine and chemokine production by astrocytes. Pretreatment with the NF-κB inhibitor parthenolide provided evidence that Tat±morphine-induced …

Long Lasting Synchronization Of Calcium Oscillations By Cholinergic Stimulation In Isolated Pancreatic Islets, Min Zhang, Bernard Fendler, Bradford Peercy, Pranay Goel, Richard Bertram, Arthur Sherman, Leslie Satin

Pharmacology and Toxicology Publications

Abstract

Individual mouse pancreatic islets exhibit oscillations in [Ca²⁺]_i and insulin secretion in response to glucose in vitro, but how the oscillations of a million islets are coordinated within the human pancreas in vivo is unclear. Islet to islet synchronization is necessary, however, for the pancreas to produce regular pulses of insulin. To determine whether neurohormone release within the pancreas might play a role in coordinating islet activity, [Ca²⁺]_i changes in 4–6 isolated mouse islets were simultaneously monitored before and after a transient pulse of a putative synchronizing agent. The degree of synchronicity was …

Communication Skills Instruction Utilizing Interdisciplinary Peer Teachers: Program Development And Student Perceptions, Sharon K. Lanning, Sonya L. Ranson, Rita M. Willett

Periodontics Publications

Lack of curricular time, faculty time, and funding are potential limitations for communication skills training in dentistry. Interdisciplinary collaboration amongst health care faculties could address these limitations. This article describes the development, implementation, and student perceptions of a communication skills program in dentistry. The program has four components: Knowledge, Observation, Simulation, and Experience (KOSE) and spans over the second and third years of dental school. KOSE allows students to obtain knowledge of and observe effective communication skills and practice these skills in the simulated and nonsimulated environment. A key feature of KOSE is the utilization of fourth-year medical and dental …

Nadph Oxidase As A Therapeutic Target In Alzheimer's Disease, Michelle L. Block

Anatomy and Neurobiology Publications

At present, available treatments for Alzheimer's disease (AD) are largely unable to halt disease progression. Microglia, the resident macrophages in the brain, are strongly implicated in the pathology and progressively degenerative nature of AD. Specifically, microglia are activated in response to both β amyloid (Aβ) and neuronal damage, and can become a chronic source of neurotoxic cytokines and reactive oxygen species (ROS). NADPH oxidase is a multi-subunit enzyme complex responsible for the production of both extracellular and intracellular ROS by microglia. Importantly, NADPH oxidase expression is upregulated in AD and is an essential component of microglia-mediated Aβ neurotoxicity. Activation of …

A Synaptic Nidogen: Developmental Regulation And Role Of Nidogen-2 At The Neuromuscular Junction, Michael A. Fox, Matthew Sp Ho, Neil Smyth, Joshua R. Sanes

Anatomy and Neurobiology Publications

Background

The skeletal neuromuscular junction is a useful model for elucidating mechanisms that regulate synaptogenesis. Developmentally important intercellular interactions at the neuromuscular junction are mediated by the synaptic portion of a basal lamina that completely ensheaths each muscle fiber. Basal laminas in general are composed of four main types of glycosylated proteins: laminins, collagens IV, heparan sulfate proteoglycans and nidogens (entactins). The portion of the muscle fiber basal lamina that passes between the motor nerve terminal and postsynaptic membrane has been shown to bear distinct isoforms of the first three of these. For laminins and collagens IV, the proteins are …

Arabidopsis Mrna Polyadenylation Machinery: Comprehensive Analysis Of Protein-Protein Interactions And Gene Expression Profiling, Arthur G. Hunt, Ruqiang Xu, Balasubrahmanyam Addepalli, Suryadevara Rao, Kevin P. Forbes, Lisa R. Meeks, Denghui Xing, Min Mo, Hongwei Zhao, Amrita Bandyopadhyay, Lavanya Dampanaboina, Amanda Marion, Carol Von Lanken, Qingshun Quinn Li

Anatomy and Neurobiology Publications

Background

The polyadenylation of mRNA is one of the critical processing steps during expression of almost all eukaryotic genes. It is tightly integrated with transcription, particularly its termination, as well as other RNA processing events, i.e. capping and splicing. The poly(A) tail protects the mRNA from unregulated degradation, and it is required for nuclear export and translation initiation. In recent years, it has been demonstrated that the polyadenylation process is also involved in the regulation of gene expression. The polyadenylation process requires two components, the cis-elements on the mRNA and a group of protein factors that recognize the cis …

Accelerated Exchange Of Exon Segments In Viperid Three-Finger Toxin Genes (Sistrurus Catenatus Edwardsii; Desert Massasauga), Robin Doley, Susanta Pahari, Stephen P. Mackessy, R. Manjunatha Kini

Biochemistry and Molecular Biology Publications

Background Snake venoms consist primarily of proteins and peptides showing a myriad of potent biological activities which have been shaped by both adaptive and neutral selective forces. Venom proteins are encoded by multigene families that have evolved through a process of gene duplication followed by accelerated evolution in the protein coding region.

Results Here we report five gene structures of three-finger toxins from a viperid snake, Sistrurus catenatus edwardsii. These toxin genes are structured similarly to elapid and hydrophiid three-finger toxin genes, with two introns and three exons. Both introns and exons show distinct patterns of segmentation, and the insertion/deletion …

Primary Cultured Fibroblasts Derived From Patients With Chronic Wounds: A Methodology To Produce Human Cell Lines And Test Putative Growth Factor Therapy Such As Gmcsf, Harold Brem, Michael S. Golinko, Olivera Stojadinovic, Arber Kodra, Robert F. Diegelmann, Sasa Vukelic, Hyacinth Entero, Donald L. Coppock, Marjana Tomic-Canic

Biochemistry and Molecular Biology Publications

Background Multiple physiologic impairments are responsible for chronic wounds. A cell line grown which retains its phenotype from patient wounds would provide means of testing new therapies. Clinical information on patients from whom cells were grown can provide insights into mechanisms of specific disease such as diabetes or biological processes such as aging.

The objective of this study was 1) To culture human cells derived from patients with chronic wounds and to test the effects of putative therapies, Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) on these cells. 2) To describe a methodology to create fibroblast cell lines from patients with chronic …

Predicting Outcome After Traumatic Brain Injury: Development And International Validation Of Prognostic Scores Based On Admission Characteristics, Ewout W. Steyerberg, Nino Mushkudiani, Pablo Perel, Isabella Butcher, Juan Lu, Gillian S. Mchugh, Gordon D. Murray, Anthony Marmatou, Ian Roberts, J. D. F. Habbema, Andrew I. R. Maas

Neurosurgery Publications

Background

Traumatic brain injury (TBI) is a leading cause of death and disability. A reliable prediction of outcome on admission is of great clinical relevance. We aimed to develop prognostic models with readily available traditional and novel predictors.

Methods and Findings

Prospectively collected individual patient data were analyzed from 11 studies. We considered predictors available at admission in logistic regression models to predict mortality and unfavorable outcome according to the Glasgow Outcome Scale at 6 mo after injury. Prognostic models were developed in 8,509 patients with severe or moderate TBI, with cross-validation by omission of each of the 11 studies …

Inflammatory And Coagulation Biomarkers And Mortality In Patients With Hiv Infection, Lewis H. Kuller, Russell Tracy, Waldo Belloso, Stephane De Wit, Fraser Drummond, H. Clifford Lane, Bruno Ledergerber, Jens Lundgren, Jacqueline Neuhaus, Daniel Nixon, Nicholas I. Paton, James D. Neaton

Internal Medicine Publications

Background

In the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CD4-guided antiretroviral treatment (ART) (drug conservation [DC]) than continuous ART (viral suppression [VS]).

We hypothesized that increased HIV-RNA levels following ART interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis.

Methods and Findings

Stored samples were used to measure six biomarkers: high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), amyloid A, amyloid P, D-dimer, and prothrombin fragment 1+2. Two studies were conducted: (1) a nested case–control study for studying biomarker associations with mortality, and (2) a study to compare DC and …

Metformin For The Treatment Of The Polycystic Ovary Syndrome, John E. Nestler

Internal Medicine Publications

This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the author’s clinical recommendations.

A 23-year-old woman with known polycystic ovary syndrome visits her family physician. She has taken oral contraceptive pills in the past but did not tolerate them and is not currently receiving any treatment. She has three or four menstrual …

Treatment Of Patients With The Hypereosinophilic Syndrome With Mepolizumab, Marc E. Rothenberg, Amy D. Klion, Florence E. Roufosse, Jean E. Kahn, Peter F. Weller, Hans-Uwe Simon, Lawrence B. Schwartz, Lanny J. Rosenwasser, Johannes Ring, Elaine F. Griffin, Ann E. Haig, Paul I. H. Frewer, Jacqueline M. Parkin, Gerald J. Gleich

Internal Medicine Publications

BACKGROUND

The hypereosinophilic syndrome is a group of diseases characterized by persistent blood eosinophilia, defined as more than 1500 cells per microliter with end-organ involvement and no recognized secondary cause. Although most patients have a response to corticosteroids, side effects are common and can lead to considerable morbidity.

METHODS

We conducted an international, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of an anti–interleukin-5 monoclonal antibody, mepolizumab, in patients with the hypereosinophilic syndrome. Patients were negative for the FIP1L1–PDGFRA fusion gene and required prednisone monotherapy, 20 to 60 mg per day, to maintain a stable clinical status and a …

An Integrative Genomic And Epigenomic Approach For The Study Of Transcriptional Regulation, Maria E. Figueroa, Mark A. Reimers, Reid F. Thompson, Kenny Ye, Yushan Li, Rebecca R. Selzer, Jakob Fridriksson, Elisabeth Paietta, Peter Wiemik, Ronald D. Green, John M. Greally, Ari Melnick

Biostatistics Publications

The molecular heterogeneity of acute leukemias and other tumors constitutes a major obstacle towards understanding disease pathogenesis and developing new targeted-therapies. Aberrant gene regulation is a hallmark of cancer and plays a central role in determining tumor phenotype. We predicted that integration of different genome-wide epigenetic regulatory marks along with gene expression levels would provide greater power in capturing biological differences between leukemia subtypes. Gene expression, cytosine methylation and histone H3 lysine 9 (H3K9) acetylation were measured using high-density oligonucleotide microarrays in primary human acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) specimens. We found that DNA methylation and …

Prolonged Therapy Of Advanced Chronic Hepatitis C With Low-Dose Peginterferon, Adrian M. Di Bisceglie, Mitchell L. Shiffman, Gregory T. Everson, Karen L. Lindsay, James E. Everhart, Elizabeth C. Wright, William M. Lee, Anna S. Lok, Herbert L. Bonkovsky, Timothy R. Morgan, Marc G. Ghany, Chihiro Morishima, Kristin K. Snow, Jules L. Dienstag

VCU Health Publications

Background

In patients with chronic hepatitis C who do not have a response to antiviral treatment, the disease may progress to cirrhosis, liver failure, hepatocellular carcinoma, and death. Whether long-term antiviral therapy can prevent progressive liver disease in such patients remains uncertain.

Methods

We conducted a randomized, controlled trial of peginterferon alfa-2a at a dosage of 90 μg per week for 3.5 years, as compared with no treatment, in 1050 patients with chronic hepatitis C and advanced fibrosis who had not had a response to previous therapy with peginterferon and ribavirin. The patients, who were stratified according to stage of …

Accuracy Of Ct Colonography For Detection Of Large Adenomas And Cancers, Daniel C. Johnson, Mei-Hsiu Chen, Alicia Y. Toledano, Jay P. Heiken, Abraham Dachman, Mark D. Kuo, Christine O. Menias, Betina Siewert, Jugesh I. Cheema, Richard G. Obregon, Jeff L. Fidler, Peter Zimmerman, Karen M. Horton, Kevin Coakley, Revathy B. Iyer, Amy K. Hara, Robert A. Halvorsen Jr, Giovanna Casola, Judy Yee, Benjamin A. Herman, Lawrence J. Burgart, Paul J. Limburg

Radiology Publications

Background

Computed tomographic (CT) colonography is a noninvasive option in screening for colorectal cancer. However, its accuracy as a screening tool in asymptomatic adults has not been well defined.

Methods

We recruited 2600 asymptomatic study participants, 50 years of age or older, at 15 study centers. CT colonographic images were acquired with the use of standard bowel preparation, stool and fluid tagging, mechanical insufflation, and multidetector-row CT scanners (with 16 or more rows). Radiologists trained in CT colonography reported all lesions measuring 5 mm or more in diameter. Optical colonoscopy and histologic review were performed according to established clinical protocols …

Gap Junction Coupling And Calcium Waves In The Pancreatic Islet, Richard K.P. Benninger, Min Zhang, W. Steven Head, Leslie S. Satin, David W. Piston

Pharmacology and Toxicology Publications

Abstract

The pancreatic islet is a highly coupled, multicellular system that exhibits complex spatiotemporal electrical activity in response to elevated glucose levels. The emergent properties of islets, which differ from those arising in isolated islet cells, are believed to arise in part by gap junctional coupling, but the mechanisms through which this coupling occurs are poorly understood. To uncover these mechanisms, we have used both high-speed imaging and theoretical modeling of the electrical activity in pancreatic islets under a reduction in the gap junction mediated electrical coupling. Utilizing islets from a gap junction protein connexin 36 knockout mouse model together …

Protocol: Streamline Cloning Of Genes Into Binary Vectors In Agrobacterium Via The Gateway® Topo Vector System, Ruqiang Xu, Qingshun Quinn Li

Anatomy and Neurobiology Publications

Background

In plant functional genomic studies, gene cloning into binary vectors for plant transformation is a routine procedure. Traditionally, gene cloning has relied on restriction enzyme digestion and ligation. In recent years, however, Gateway^® cloning technology (Invitrogen Co.) has developed a fast and reliable alternative cloning methodology which uses a phage recombination strategy. While many Gateway- compatible vectors are available, we frequently encounter problems in which antibiotic resistance genes for bacterial selection are the same between recombinant vectors. Under these conditions, it is difficult, if not sometimes impossible, to use antibiotic resistance in selecting the desired transformants. We have, …

It's About The People, Edward F. Ansello

Director's Editorials from Age in Action

The Virginia Center on Aging celebrates 30 years and the people who have made accomplishments possible.

Geriatric Training And Education (Gte) Projects, Edward F. Ansello

Director's Editorials from Age in Action

The Geriatric Training and Education (GTE) initiative is supporting 15 different projects in the current fiscal year that are affecting Virginians in each region, from certified nursing assistants to family caregivers of relatives with dementia to long-term care staff helping elders at the end of life.

Tackling Elder Abuse, Edward F. Ansello

Director's Editorials from Age in Action

The Central Virginia Training Alliance to Stop Elder Abuse, Neglect, and Exploitation was selected to pilot a three-year training initiative for criminal justice professionals on elder abuse, neglect, and exploitation. Our overall intention is to improve the expertise of each component in investigating and prosecuting maltreatment against our elders.

Priorities In A Time Of Crisis, Edward F. Ansello

Director's Editorials from Age in Action

Now, amidst economic stress, is the time to defend certain sections of the budget, including the protection of those among us who are least able.

No Wrong Door: Virginia’S Key Strategic Initiative For Long-Term Care, Molly Huffstetler

Case Studies from Age in Action

Educational Objectives

1. Describe the rationale, current activities, and vision for No Wrong Door as it pertains to seniors, adults with disabilities, and their caregivers throughout Virginia.

2. Demonstrate the positive potential for collaboration among local long-term care service providers, both public and private.

3. Illustrate the benefits of coordinating long-term care services for an individual through Virginia’s No Wrong Door.

Confident Living Program For Senior Adults Experiencing Combined Vision And Hearing Loss, Paige Berry, Mia Kelley-Bock, Christine Reid

Case Studies from Age in Action

Educational Objectives

1. Identify needs common among older adults who have combined vision and hearing loss.

2. Describe a model program that provides information, resources, and training to older adults experiencing combined vision and hearing loss.

3. Describe how the program benefits not only consumers, but also family, friends, caregivers, students, and service providers.

Making Affordable Assisted Living Work: The Mountainside Senior Living Story, Cheryl Cooper, Gordon Walker

Case Studies from Age in Action

Educational Objectives

1. Describe the challenges of providing affordable assisted living in Virginia.

2. Describe the experience of the Jefferson Area Board for the Aging (JABA), an Area Agency on Aging, in becoming owner and operator of an assisted living facility.

3. Describe the culture change that made Mountainside a unique and award-winning facility.

The Aging Together Partnership: Collaborating To Improve Quality Of Life For Older Adults, April Holmes, Chris Miller

Case Studies from Age in Action

Educational Objectives 1. Demonstrate how the Aging Together experience improves services for older adults. 2. Describe the partnership structure and participation that makes this an effective model for community services amidst demographic changes. 3. Illustrate tangible service improvements resulting from Aging Together collaborations.

Dengue Virus Pathogenesis In Mouse Central Nervous System: Studies On Host Response To Dengue Virus Infection, Juliano Bordignon, Christian Probst, Ana Luiza P. Mosimann, Vanessa Stella, Daniela Pavoni, Gregory A. Buck, Paul Fawcett, Silvio M. Zanata, Lucia Noronha, Marco Krieger, Claudia Nunes Duarte Dos Santos

Microbiology and Immunology Publications

Dengue virus (DENV) causes a self-limiting fever (DF) or severe hemorrhagic fever/shock-syndrome (DHF/DSS). Recently, clinical profile of DENV infection is changing, and neurological manifestations are becoming frequent. We previously demonstrated that mutations on E and NS3 proteins may account for DENV neurovirulence for mice. To validate the involvement of the observed mutations in the appearance of neurovirulent viral phenotypes, we constructed cDNA infectious clones encompassing the observed mutations. Aiming to determine host response to infection with neurovirulent and parental strains of DENV-1, we used a Mus musculus biochip (Virginia Commonwealth University) encompassing whole mouse genome. Newborn Swiss mice were infected …

Impaired Clearance Of Methotrexate In Organic Anion Transporter 3 (Slc22a8) Knockout Mice: A Gender Specific Impact Of Reduced Folates, Adam L. Vanwert, Douglas H. Sweet

Pharmaceutics Publications

Purpose

To elucidate the role of the renal basolateral transporter, Oat3, in the disposition of methotrexate.

Materials and Methods

Chinese hamster ovary cells expressing mouse Oat3 were used to determine kinetics and specificity of inhibition of methotrexate transport. Methotrexate clearance was then examined in vivo in wildtype and Oat3 knockout mice.

Results

NSAIDs, ß-lactams, and uremic toxins inhibited mOat3-mediated methotrexate uptake by 70–100%, while folate, leucovorin, and 5-methyltetrahydrofolate inhibited transport by 25–50%. A Km of 60.6±9.3 μM for methotrexate transport was determined. Oat3 knockout mice exhibited reduced methotrexate-to-inulin clearance ratios versus wildtype. Male wildtype mice, but not knockouts or …